HU201030B - Process for production of pharmaceutically active compounds - Google Patents

Description

The present invention relates to novel compounds of formula (I) having an angiotensin converting enzyme inhibiting activity, wherein:

Y is sulfur, oxygen or NR9 - wherein when Y is sulfur or NR9, n is 1, if Y is oxygen or sulfur, n is 0, R9 is C1-4 alkyl -,

R 3 is C 1-6 alkyl, C 3-10 cycloalkyl, -SR 10, pyridyl, furyl, morpholino, -NR 4 R 5, phenyl or C 7-10 phenylalkyl, naphthyl, while phenyl is optionally C 1 -C 4 alkyl, trifluoromethyl, halogen, C 1 -C 4 alkoxy, or -SR

ZCHRCON

COOH

The scope of the specification is: 8 pages, optionally substituted with a group of the formula: R 1 is C 1 -C 4 alkyl, R 4 is hydrogen, R 8 is C 1 -C 4 alkyl, R 10 is C 1 -C 4 alkyl,

R is hydrogen, (C 1 -C 4) alkyl or (C 1 -C 6) alkyl substituted with amino;

Z is R ₂ CH (COOH) NH- or R ₁ SCH 2 - wherein R 1 is hydrogen or ReCO-, - where Re is C 1 -C 4 alkyl, - R ₂ is C 1 -C 5 alkyl, or 7 to 10 carbon atoms. C 1 -C 4 phenylalkyl; and their pharmaceutically acceptable salts, C 1 -C 4 alkyl esters or C 7 -C 10 phenylalkyl esters.

(1)

HU 201 030 B

-1HU 201030 Β

The present invention relates to novel, advantageous oxa and thiadiazoles, thiadiazines and triazines having, for example, ACE (adrenal cortex extract) inhibitory activity.

Many angiotensin converting enzyme (ACE) inhibitors have become known; such as those described in U.S. Pat. French Patent No. 0012401 and European Patent No. 0012401.

The compounds of the present invention are represented by formula (I). in this

Y is sulfur, oxygen or NR9 - wherein when Y is sulfur or NR9, n is 1, if Y is oxygen or sulfur, n is 0, R9 is C1-C4 alkyl,

R 3 is C 1-6 alkyl, C 3-10 cycloalkyl, -SR 10, pyridyl, furyl, morpholino, -NR 4 R 5, phenyl or C 7-10 phenylalkyl, naphthyl, while phenyl may be optionally substituted with C 1 -C 4 alkyl, trifluoromethyl, halogen, C 1 -C 4 alkoxy, or -SR 6 alkyl, R 1 is C 1 -C 4 alkyl, R 4 is hydrogen, C 1 -C 4 alkyl, R 1 -C 4 alkyl,

R is hydrogen, (C 1 -C 4) alkyl or (C 1 -C 6) alkyl substituted with amino;

Z is R ₂ CH (COOH) NH- or R ₁₅ CH ₂ - wherein R 1 is hydrogen or R 5 CO-, wherein R 8 is C 1 -C 4 alkyl, - R ₂ is C 1 -C 5 alkyl, or -C 10 phenylalkyl.

The process of the present invention also comprises the preparation of pharmaceutically acceptable salts, C 1-4 alkyl or C 7-10 phenylalkyl esters of the compounds of formula (I).

According to the present invention, the pharmaceutically acceptable salts and said esters of the compounds of formula (I), wherein Υ, η, Z, R and R3 are as defined, are prepared by reacting a compound of formula (II) wherein Y, n and R3 are as defined -, its salt ester or tautomeric form is reacted with an optionally protected compound of formula (III) wherein Z and R are as defined and X is a leaving group - optionally converting a compound of configuration R into S , cleaving the amino protecting group and, if desired, removing the thiol and / or carboxylic acid protecting group or groups from a compound of formula (I) and / or converting a compound of formula (I) into a pharmaceutically acceptable salt or ester or in the opposite direction.

In this process, the protecting group can be any known protecting group used in peptide synthesis and is removed in a manner known in the art for peptide synthesis. Examples of such protecting groups include straight or branched C 1-6 -alkoxy such as tert-butyloxy or C 7-12 phenylalkoxy such as benzyl 2 oxy. These groups are removed by hydrolysis such as basic hydrolysis or cleavage such as trifluoroacetic acid or hydrogenation such as palladium on charcoal.

The amino protecting group may be C2-C7 alkyloxycarbonyl such as tert-butyloxycarbonyl or C8-C13 phenylalkyloxycarbonyl such as benzyloxycarbonyl. Preferably, starting compounds are used in which the carboxyl group is also protected.

The substituent X may be halogen, for example bromine or chlorine. The reaction may be carried out in a solvent inert to the reaction, such as acetonitrile, at a temperature of 0 to 100 ° C, preferably about 30 ° C. The reaction is preferably carried out under basic conditions, for example in the presence of triethylamine or polyvinylpyridine.

The R> S configuration conversion may be carried out in a solvent inert to the reaction, such as acetonitrile, at a temperature between 0 ° C and the boiling point of the solvent, preferably at 20-30 ° C. The reaction may be carried out under anhydrous conditions such as molecular sieve and in the presence of a base such as pyrrolidine.

Salts are prepared by reacting the free acid or ester thereof or the free base with one or more equivalents of the appropriate base or acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is insoluble or in a solvent in which the salt is soluble, such as ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo or freeze-dried. The reaction may be a decomposition reaction or it may be carried out on an ion exchange resin.

Acceptable salts of the compounds of formula I are known salts.

The starting compounds used in the processes described above are known or can be prepared in a known manner. For example, compounds of formula II wherein n is 0 may be prepared by reacting a compound of formula IV, wherein Y and R3 are as defined, or a salt thereof with glyoxylic acid, a salt, ester or protected derivative thereof. such as alcohol, such as ethanol at room temperature.

The compounds of formula II, wherein Y and R3 are as defined and n is 0, may exist in the tautomeric form of formula VII, wherein Y and R3 are as defined, or as a salt, ester or protected derivative thereof. .

Compounds of formula (II) wherein n is 1 are prepared by reacting a compound of formula (IV) wherein Y and R3 are as defined, or a salt thereof with a compound of formula (V): or a salt thereof, an ester or a protected derivative thereof, for example in a reaction solvent such as benzene at a temperature of 0-120 ° C, preferably 0-25 ° C, with a base such as 1,5-diazabicyclo [4.3.0] non-5 in the presence of je-2EN 201030 Β.

Compounds of general formula (III) wherein Z, R and X are as defined are prepared from the corresponding acids of formula (VI) or derivatives thereof in known manner.

The compounds of formula (I), wherein Y, η, Z, R and R ₃ are as defined, and the intermediates are isolated from the reaction mixture in a known manner.

Compounds of formula (II) wherein Y, n and R ₃ are as defined herein, salts, esters and protected derivatives thereof are useful intermediates.

Pharmaceutically acceptable esters include C 1 -C 4 alkyl esters and benzyl alcohol esters.

Preferred compounds of formula (I) are those wherein Z is R2CH (COOH) NH-.

When Z is R ₂ CH (COOH) NH-, the moiety -NHCHRCO- is preferably derived from a naturally occurring amino acid. Preferably the carboxyl group represented by Z is in the form of a C 1 -C 4 alkyl ester such as ethyl ester.

The alkyl groups may be linear or branched, preferably R is C 1-4 alkyl or C 1-6 aminoalkyl such as methyl or aminobutyl.

Preferably R2 is n-propyl or phenylethyl.

Re and Rio are preferably methyl.

When R ₃ is alkyl, it may be straight or branched chain, or mono-, bi- or tricycloalkyl, for example up to 10 carbon atoms. Preferably R ₃ is C 1-6 alkyl or C 3-10 cycloalkyl, particularly preferably C 1-6 alkyl or C 3-6 cycloalkyl. R _{3 is} particularly tert-butyl or cyclohexyl.

Y is preferably oxygen, or particularly preferably sulfur.

Preferably, n is 0.

Preferably, the carboxyl group on the Y-containing heterocyclic ring is not in the form of a derivative.

Preferably R1 is hydrogen.

Particularly preferred are compounds of formula I wherein Z is R2CH (COOH) NH-, Y is sulfur, R is methyl or aminobutyl, n is 0, R2 is n-propyl or phenylethyl alkyl and R ₃ is tert-butyl, and their salts and esters.

Preferred salts of the compounds of the formula I are maleate, hydrochloride, ammonium and dicyclohexylammonium salts.

Compounds of formula (I) wherein Y, η, Z, R and R ₃ are as defined herein may have one or more asymmetric carbon atoms and may therefore be present as optical isomers and / or diastereomeric isomers. The diastereoisomers and optical isomers may be separated in conventional manner. Preference is given to compounds of formula I in which the asymmetric carbon atom has the S configuration.

The compounds of the present invention are more advantageous than the known structurally related compounds because they are more effective, cause fewer side effects, last longer, are more readily absorbed, less toxic, have a different distribution in organ tissues, and have other beneficial properties.

The compounds of the present invention inhibit the angiotensin converting enzyme.

The compounds of the present invention are thus useful in the treatment of patients with hypertension.

The following experiment was performed.

A group of spontaneously hypertensive rats (SHRs) were fully acclimatized to each assay during a training period of at least three weeks. Only rats were used for the test, which showed a normal sensitivity to standard compounds (Nifedipine 10 ^"5 mol / kg P °) ·

The animals were fasted overnight for the duration of the experiment, but were free to drink water and 6% glucose solution. Twelve SHRs were caged and placed in a warm-air incubator (30 ± 2 ° C) for 20 minutes, after which the pulse was measured at the tail. Rat blood pressure was measured using the cuff surrounding the anterior tail. The cuff surrounding the tail was inflated by an automatic device and connected to a chart recorder. The point at which the blood pressure signal disappeared when the cuff was inflated was used as a measurement of hysterectomy. The rats were then divided into two groups of six, so that the two groups had approximately the same hysterectomy blood pressure. Hydrochlorothiazide was added to both groups at 2x10 ⁵ mol / kg (po). One group (control) received vehicle (polyethylene glycol, 300 molar weight; 1 ml / kg po), while the other group (test) received a test compound solution of polyethylene glycol (1 ml / kg po). Hysterectomy blood pressure was measured 24 hours after administration of the test compound or vehicle,

Compounds were compared with captopril, enalapril and delapril.

The following compounds were tested as described and obtained the following results:

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Compound Dose (10 'to ⁵ mol / kg' ¹ ) Systolic blood pressure drop% captopril 10 5 enalapril 1 7 delapril Example 1 10 9 compound 6n. example 1 26 compound 6s. example 1 25 compound Example 4 1 37 compound 6q. example 1 17 compound 1 14

The invention is further illustrated by the following Examples, without limitation. The temperatures indicated are in ° C.

Example 1

5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-3-phenyl 25-propyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole Preparation of 2- (S) -carboxylic acid

a) Preparation of benzyl 5- (tert-butyl) -2,3-dihydro-1,3,4-thiadiazole-2-carboxylate

A solution of tert-butylcarbothioic acid hydrazide (0.7 g) and 30 benzylglyoxylate (1 g) in ethanol (15 mL) was stirred for 16 hours under nitrogen. The solvent was evaporated and the residue was purified by chromatography (petroleum ether / ethyl acetate as eluent) to give the title compound (1.1 g) as a gum.

b) Benzyl-5- (tert-butyl) -3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-1,3,4- Preparation of thiadiazole-2- (R) -carboxylate

N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine 40 n (0.57 g) and 1-hydroxybenzotriazole (0.28 g) in dichloromethane (40 ml) The reaction mixture was treated with a solution of the product of step a) (1.14 g) in dichloromethane (5 mL). The resulting reaction mixture was treated with dicyclohexylcarbodiimide (0.42 45)

g) was added and the resulting mixture was stirred at room temperature under nitrogen for 16 hours.

The resulting suspended solid was removed by filtration and the filtrate was evaporated to give a gum. The residue was purified by chromatography 50 to give the title compound (0.82 g) as an oil.

Mass Spectrum (FAB): M ⁺ 540 (base peak 91).

The molecular weight of C29H37N25DS is 559.

c) Benzyl-5- (tert-butyl) -3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-1,3,4- Preparation of thiadiazole-2- (S) -carboxylate

A solution of the product from step b (1.0 g) and pyrrolidine 60 (1 g) in dry acetonitrile (30 mL) was treated with ground 3A molecular sieve and the reaction mixture was stirred for 6 hours at room temperature. The volatiles were evaporated and the resulting

The S, S, S isomer is separated from the polar S, S, R isomer 65 by chromatography (petroleum ether / ethyl acetate). The title product (0.4 g) was isolated as a pure gum.

Mass Spectrum: M ⁺ 539 (base peak 234).

The molecular weight for C29H37N35DS is 539.

d) 5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole -2- Preparation of (S) -carboxylic acid

A solution of the product of Example c (0.67 g) in ethanol (100 mL) was treated with 10% palladium on carbon (0.6 g) and the resulting mixture was stirred for 16 hours under 1 atmosphere of hydrogen gas. The catalyst was removed by filtration and the filtrate was concentrated to about 2 mL. The cooled solution gave the title compound (0.3 g) as white crystals, m.p. 165-168 ° C.

Elemental Analysis for C22H31N3O5S:

Found: C, 58.80; H, 6.90; N, 9.35; S, 7.13. Found: C, 58.87; H, 6.89; N, 9.34; S, 7 21%.

Mass Spectrum (FAB): M ⁺ 450 (a ^{'P cs} UCS 234).

The molecular weight for C22H31N35DS is 449.

Example 2

5- (tert-Butyl) -3- {Na- [1- (S) -carboxy-3-phenylpropyl] -L-lysyl} -2,3-dihydro-1,3,4-thiadiazole-2- (S) ) Carboxylic acid

a) Preparation of benzyl 2-hydroxy-4-phenylbutanoate

A mixture of 2-hydroxy-4-phenylbutanoic acid (20.4 g), triethylamine (15.9 ml) and benzyl bromide (12.75 ml) in ethyl acetate (61 ml) was heated at reflux for 16 hours. The resulting solution was cooled and poured into a mixture of water and ether. The separated organic extract was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by chromatography (petroleum ether / ethyl acetate) to give the title product as a yellow oil (14 g).

Mass Spectrum: M ⁺ 270 (base peak 91).

The molecular weight for C17H18O3 D is 270.

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b) Preparation of N ^e - (Benzyloxycarbonyl) -N ^a - [1- (S) -benzyloxycarbonyl-3-phenylpropyl] -L-lysine hydrochloride

A solution of the product of Example a) (13.8 g) and pyridine (6.6 mL) in dichloromethane (136 mL) was added over 4 hours under a nitrogen atmosphere to trifluoromethanesulfonic anhydride (12.9 mL) in dichloromethane (136 mL). prepared at 5 ° C. After a further 0.5 hours, the resulting solution was washed with water, dried over magnesium sulfate, filtered and the filtrate was evaporated.

The residue was taken up in dichloromethane (136 ml) and a solution of N ^e -benzyloxycarbonyl-L-lysine tert -butyl ester (15.5 g) and triethylamine (6.5 ml) ksézített dichloromethane (136 mL) was added . The reaction mixture was stirred for 1 hour at room temperature, refluxed for 2.5 hours, cooled, washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was chromatographed (ether / petroleum ether) to isolate the more polar SS isomer.

A solution of the resultant SS-tert-butyl ester (0.5 g) in ether (15 mL) was cooled to + 15 ° C and saturated with hydrogen chloride gas for 2 hours. The resulting solution was stirred for an additional 18 hours at room temperature and the solvent was evaporated. The residue was triturated with ether to give the title compound as a white solid (0.39 g).

The fast atomic bomb mass spectrum is M ⁺ 533 (base peak 91).

The molecular weight for C31H36N2O6 is 532.

c) 1-Benzyl-3- ^{N? - (tert Beaziloxi) ^PR -N - [l (S) -benzilorikarbonil-3-phenylpropyl] -L-lysine} -5- (tert-butyl) -2, Preparation of 3-dihydro-1,3,4-thiadiazole-2- (R) -carboxylate

A solution of the SS product of Example b) (5.68 g) and l-hydroxybenzotriazole (1.35 g) in dichloromethane (85 mL) was stirred with the product of Example 1 a) (5.87 g). ) in dichloromethane (60 mL). To the resulting reaction mixture was added a solution of dicyclohexylcarbodiimide (2.1 g) in dichloromethane (85 mL) over 5 minutes, and the resulting mixture was stirred at room temperature under nitrogen for 18 hours. To the reaction mixture was added triethylamine (1.4 mL) and the suspended solid was removed by filtration. The filtrate was evaporated and the residue was purified by chromatography. The title compound was obtained as an oil (2.1 g).

The mass spectrum for fast atom bombardment is M ⁺ 793 (base peak 91).

C45HS2N4O7S has a molecular weight of 792,

d) Benzyl 3- ^{N? - (benzyloxycarbonyl) ^-N # - [l (S) -benzyloxycarbonyl-3-phenylpropyl] -L-lysyl} -5- (crc t-butyl) -2, Preparation of 3-dihydro-1,3,4-thiadiazole-2- (S) -carboxylate

A solution of the product of Example c (2.1 g) and pyrrolidine (1.6 mL) in dry acetonitrile (60 mL) was treated with milled 3A molecular sieve at room temperature. The volatiles were evaporated and the SSS isomer was separated from the polar SSR isomer by chromatography. The title SSS product (0.47 g) was isolated as a clear oil.

The mass spectrum for fast atom bombardment is M ⁺ 793 (base peak 91).

The C4sHs2N4O ⁷ S Formula equivalent molecular weight 792nd

e) 5- (tert-Butyl) -3- {N '- [1- (S) -carboxy-3-phenylpropyl] -L-lysyl} -2,3-dihydro-1,3,4-thiadiazole-2 - Preparation of (S) carboxylic acid

A solution of the product of Example d) (1.1 g) in ethanol (90 ml) was treated with 10% palladium on carbon (0.9 g) and the reaction mixture was stirred for 1 hour under 1 atmosphere of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated. The residue was crystallized from a mixture of tetrahydrofuran and ethanol to give a white solid (0.24 g), mp 180-190 ° C with slow decomposition.

Elemental Analysis for C23H34N4O5S. According to the formula 0.77 H2O:

Calculated: C, 56.11; H, 7.23; N, 11.39; S, 6.51.

H ₂ O, 2.82% Found: C: 55.86, H: 6.97, N: 11.24, S: 6.56, H2 O: 2.83%.

The mass spectrum for rapid atomic bombardment is M 479 (base peak 84).

The molecular weight for C23H24N4O5S is 478.

₍ Example 3

5- (tert-butyl) -3- ^(N - [l- (S) -ethoxycarbonyl-butyl] -L-alanyl} -2,3-dihydro-3,4-tiadiazoJ-2- (S) -char, bonic acid preparation

a) Preparation of ethyl 2 - {[(trifluoromethane) sulfonyl] oxy} pentanoate

A solution of pyridine (11.9 g) in dry dichloromethane (500 mL) was stirred rapidly at -22 ° C while trifluoromethanesulfonic anhydride (40.5 g) was added dropwise. After the addition, the white slurry obtained was stirred at -22 ° C for 15 minutes and then a solution of ethyl 2-hydroxypentanoate (16.8 g) in dichloromethane was added at the same temperature for 2 minutes. After allowing the reaction mixture to warm to room temperature, the reaction mixture was stirred vigorously for one hour to precipitate a white solid, which was filtered, washed well with dichloromethane and the combined washings and filtrates evaporated to dryness. The oily residue was taken up in petroleum ether (b.p. 60-80 ° C) and passed through a short silica gel column using petroleum ether as eluent. The resulting petroleum ether solution was evaporated to dryness to give an oil (23.4 g).

NMR, CDCl 3 delta: 1.0 (3H, t), 1.32 (3H, t), 1.5 (2H, m), 2.0 (2H, m), 4.3 (2H, m), 5.12 (1H, t).

b) Preparation of N- (1-Ethoxycarbonyl-butyl) -L-alanine benzyl ester

L-Alanine benzyl ester hydrochloride (10.0 g) in dichloromethane was converted to the free base with triethylamine. The reaction mixture was evaporated to dryness and the residue was slurried with diethyl ether in several portions. The combined ethereal solutions were evaporated to dryness to give the free base as an oil

-5GB 201030 Β will stay. The resulting oil was dissolved in dichloromethane (200 mL) and triethylamine (7.2 g) was added. The resulting solution was stirred under nitrogen atmosphere at room temperature and a solution of the product of step a) (12.8 g) in dichloromethane was added dropwise over 30 minutes. The resulting reaction mixture was stirred at room temperature for 2 hours, refluxed for 2 hours, and evaporated to dryness. The oily residue was purified by chromatography on a silica gel column using petroleum ether / diethyl ether (5: 1), boiling at 60-80 ° C. The R, S isomer (4.8 g, 34%) was obtained first, followed by the S, S isomer (4.7 g, 33%).

R, S-isomer

NMR, CDCl3, delta: 0.9 (3H, t), 1.24 (3H, t), 1.30, (3H, d), 1.38 (2H, m), 1.6 (2H, m) ), 3.27 (1H,

1), 3.4 (1H, q), 4.12 (2H, m), 5.15 (2H, q), 7.35 (5H,

s).

S, S-isomer

NMR, CDCl3, delta: 0.9 (3H, t), 1.28 (3H, t), 1.38 (3H, d), 1.3-1.8 (4H, m), 3.28 ( 1H, t), 3.4 (1H, q),

4.18 (2H, m), 5.17 (2H, q), 7.35 (5H, s).

c) Preparation of N- [1- (S) -Ethoxycarbonylbutyl] -L-alanine

The S, S-diastereoisomeric benzyl ester of step b) (6.2 g) was hydrogenated in ethanol (250 mL) at 3 atmospheric pressure at room temperature for 30 minutes over 10% palladium on carbon (0.6 g). The catalyst was removed by filtration and the filtrate was evaporated to near dryness. The residue was slurried with diethyl ether and the resulting white solid was filtered and dried. This gave the title compound (3.8 g), m.p. 153-154 ° C.

Elemental analysis based on C10H19NO4:

Calculated: C, 55.29; K, 8.75; N, 6.45. Found: C, 55.62; H, 8.47; N, 6.32.

d) Benzyl-5- (tert-butyl) -3- {N- [1- (S) -ethoxycarbonyl-butyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2- (R) preparation of carboxylate

A mixture of the S, S-amino acid (0.62 g) of step c) and l-hydroxybenzotriazole (0.45 g) in dry dichloromethane (125 mL) was stirred under nitrogen at room temperature for 30 minutes. buin ') - 2,3-dihydro-1,3,4-thiad: with azole-2-carboxylate (1.6 g). Dicyclohexylcarbodiimide (0.6 g) was added to the reaction mixture, which was stirred for 18 hours, filtered and the filtrate evaporated to dryness. The residue was purified by column chromatography on silica gel using diethyl ether / petroleum ether (60-80 ° C, 1: 1) as the eluent to give the title diester as an oil (1.1 g).

NMR, CDCl3, delta: 0.9 (3H, t), 1.2-1.7 (19H,

m), 3.3 (1H, t), 4.2 (3H, m), 5.2 (2H, q), 6.18 (1H, s), 7.35 (5H, s).

c) B: Nyl-5- (tert-butyl) -3- {N- [2- (S) -ethoxycarbonyl-butyl] -L-allyl} -2,3-dihydro-1,3,4 Preparation of thiadiazole-2- (S) -carboxylate

To the S, S, R ester of step d) (1.6 g) is added pyrrolidine (1.5 mL) to the flasks in an idrogen cycle and the resulting solution is stirred for 24 hours at room temperature. This gives a 1: 1 mixture of S, S, R and S, S, S esters, which is chromatographed on a silica gel column using ethyl acetate / petroleum ether (60-80 ° C) 1: 3 as eluent. . 0.65 g of both isomers are obtained. The S, S, R isomer is recycled to give a total yield of 81%.

NMR, CDCl3, delta: 0.9 (3H, t), 1.2-1.7 (19H, m), 3.3 (1H, t), 4.2 (3H, m), 5.17 ( 2H, s), 6.18 (1H, s), 7.35 (5H, s).

f) 5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-butyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2- (S) ) -baric acid

The S, S, S-benzyl ester from step e) (1.8 g) was hydrogenated in ethanol (500 mL) over 10% palladium on carbon (1.8 g) at atmospheric pressure for 1 hour at room temperature. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with ether / petroleum ether (60-80 C) 1: 1 to give the title acid as a white solid (1.3 g), mp 183-185 ° C.

Elemental analysis for C17H29N3O5S. Based on 2.5 H2O:

Calculated: C, 47.22; H, 7.87; N, 9.72; S, 7.41. Found: C, 47.13; H, 7.89; N, 9.31; 12%.

Example 4

3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-5- (morpholin-4-yl) -1,3,4-triazide zol-2- (S) -carboxylic acid maleic salt

3- {N- [1- (S) -Exoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-5- (morpholin-4-yl) -1,3,4-thiadiazole A solution of -3- (S) -carboxylic acid (0.47 g) (prepared analogously to Example 1 from the appropriate starting compounds) in ethanol (25 ml) was treated with maleic acid (0.11 g). The solvent was evaporated. The residue was triturated with acetonitrile to give the title compound (0.31 g) as a white solid, m.p. 174-175 ° C.

Example 5

Ammonium 2,3-dihydro-3- [3-mercapto-2- (S) -methyl-1-oxopropyl] -5-phenyl-1,3,4-thiadiazole-2- (S) carboxylate monohydrate production

a) Preparation of benzyl 3- [3-acetylthio-2- (S) -methyl-1-oxopropyl] -2,3-dihydro-5-phenyl-1,3,4-thiadiazole-2-carboxylate

3-Acetylthio-2- (S) -methylpropanoyl chloride (2.3

g) In dichloromethane (30 mL), benzyl 2,3-dihydro-5-phenyl-1,3,4-thiadiazole-2-carboxylic acid is added over 5 minutes to give the appropriate starting material according to Step 1 (a). (3.6 g) and polyvinylpyridine (2.4 g) in dichloromethane (60 mL). The resulting reaction mixture was stirred at room temperature for 20 hours and then treated with additional 3-acetylthio-2- (S) -methylpropanoyl chloride (1.2 g). The reaction mixture was stirred for an additional 2 hours, filtered and the filtrate was stirred with saturated sodium bicarbonate solution for 1 hour. The organic layer was separated, washed with water, dried and evaporated. This gives a gummy material. The residue was purified by chromatography to give the title compound (4.4 g) as an oil.

b) Ammonium 2,3-dihydro-3- [3-mercapto-2 (S) -methyl-1-oxopropyl] -5-phenyl-1,3,4-thiadiazole-2- (

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Preparation of S) -carboxylate

A solution of the product of step a) (2.8 g) in methanol (50 mL) is treated dropwise with a solution of potassium hydroxide (1.3 g) in water (100 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 4 hours and then partitioned between ether and water. The separated aqueous layer was acidified with 2N hydrochloric acid and extracted with ether. The organic phase is washed with water, dried and evaporated to an oil. The residue was treated with ammonium hydroxide and the product was purified by reverse phase high performance liquid chromatography to give the title compound (0.023 g) as a white solid, m.p. 194-197 ° C.

MS: M ⁺ 310 (base 163).

The molecular weight for C13H14N2O3S2 is 310.

The compounds listed in the following Example 6 were prepared as described in the preceding Examples.

Example 6

a) 3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -Lalanyl} -2,3-dihydro-5-phenyl-1,3,4-thiadiazole-2- (S) - m.p. 180.5-182 ° C;

b) 3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -Lalanyl} -2,3-dihydro-5-phenyl-1,3,4-thiadiazole-2- (R) - k arbonic acid, M ⁺ (FAB) 470, base peak 234;

c) 2,3-Dihydro-3- (3-mercapto-1-oxo-propyl) -5-phenyl-1,3,4-thiadiazole-2-carboxylic acid, m.p. 145-146'C;

d) 3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-5- [4- (methylthio) phenyl] -1 , 3,4-thiadiazole-2- (S) -carboxylic acid, m.p. 163-164 ° C;

e) 2-Cyclohexyl-5,6-dihydro-4- (3-mercaptoxoxopropyl) -4H-1,3,4-thiadiazine-5-carboxylic acid, m.p.

f) 2,3-Dihydro-3- (3-mercapto-1-oxo-propyl) -5-phenyl-1,3,4-oxadiazole-2-carboxylic acid, m.p. 106-109 ° C;

g) 2,3-Dihydro-3- (3-mercapto-1-oxopropyl) -5- [4- (trifluoromethyl) phenyl] -1,3,4-thiadiazole-2-carboxylic acid, m.p. 93-95 ° C;

h) Benzyl 4- [3- (acetylthio) -1-oxopropyl] -5,6-dihydro-1-methyl-2-phenyl-4H-1,3,4-triazine-5-carboxylate , M ⁺ 439, base peak 93.

i) 5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-butyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2 (R) ) -carboxylic acid, m.p. 67-69 ° C;

j) 2,3-Dihydro-3- (3-mercapto-1-oxopropyl) -5-methyl-1,3,4-thiadiazole-2-carboxylic acid dicyclohexylamine salt, m.p. 150-153 ° C;

k) 5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-butyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2 (S) m.p. 124-125 ° C;

l) 3- {N- [1- (S) -Carboxy-3-phenylpropyl] -L-alanyl} -2,3-dihydro-5-phenyl-1,3,4-thiadiazole-2- (S) ) -carboxylic acid, m.p. 165-170 ° C (dec);

m) 5- (tert-Butyl) -3- {N- [1- (S) -carboxy-3-phenylpropyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2- (S) -carboxylic acid, m.p. 179-184 ° C (dec);

n) 5- (tert-Butyl) -3- {N- [1- (S) -carboxybutyl] -alanyl} -2,3-dihydro-1,3,4-thiadiazol-2- (S) - m.p. 156-159 ° C;

0) 5-Cyclohexyl-3- {N- [1- (S) -ethoxycarbonyl-3-fentanyl-propyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2- (S) 136-163 ° C;

p) 3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -Lalanyl} -2,3-dihydro-5- (pyridin-3-yl) -1,3,4-thiadiazole 2- (S) -carboxylic acid, m.p. 160-163 ° C;

q) 3- {N- [1- (S) -Ethoxycarbonyl-3-phenylpropyl] -Lalanyl} -2,3-dihydro-5-isopropyl-1,3,4-thiadiazole-2- (S) - Carboxylic acid, m.p. 151-152 ° C;

r) 3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -Lalanyl} -2,3-dihydro-5-methyl-1,3,4-thiadiazole-2- (S) carboxylic acid m.p. 161-162 ° C;

s) 5- (tert-Butyl) -3- {N '- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-lysyl} -2,3-dihydro-1,3,4-thiadiazole-2 - (S) -carboxylic acid hydrochloride, M ⁺ (FAB) 507, base peak 84;

t) 5- (tert-Butyl) -3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole; 2- (R) -carboxylic acid, m.p. 60-63 ° C;

u) 5- (tert-Butyl) -2,3-dihydro-3- (3-mercapto-l-oxo-propyl) -l, 3,4-thiadiazol-2-karbonüav, m.p .: 128 C ^e;

v) 2,3-Dihydro-3- (3-mercapto-1-oxopropyl) -5- (4-methoxyphenyl) -1,3,4-thiadiazole-2-carboxylic acid, m.p. ¹⁶⁴ ° C;

w) Ethyl 3- [3- (acetylthio) -1-oxopropyl] -2,3-dihydro-5- (methylamino) -1,3,4-thiadiazole-2-carboxylate, m.p. 102-103 ° C;

x) 2,3-Dihydro-3- (3-mercapto-1-oxopropyl) -5 (2-methylphenyl) -1,3,4-thiadiazole-2-carboxylic acid, m.p. 118-120 ' C;

y) 5- (Furan-2-yl) -2,3-dihydro-3- (3-mercaptoxoxopropyl) -1,3,4-thiadiazole-2-carboxylic acid, m.p.

z) Ethyl 3- [3- (acetylthio) -1-oxopropyl] -5- (4-chlorophenyl) -2,3-dihydro-1,3,4-thiadiazole-2-carboxylate, NMR. CDCb) characteristic peaks: δ 7.50 (4H, q, aromatic CH5), δ 2.34 (3H, s, -SCOCH3) and δ 6.30 (1H, s, heterocyclic CH);

aa) Benzyl 3- [3 - ((acetylthio) -1-oxopropyl] -5-benzyl-2,3-dihydro-1,3,4-thiadiazole-2-carboxylate, NMR (CDCl3) peak: δ 6.17 (1H, s, heterocyclic CH);

ab) Benzyl 3- [3- (acetylthio) -1-oxopropyl] -2,3-dihydro-5- (2-phenylethyl) -1,3,4-thiadiazole-2-carboxylate, NMR (CDCl3) characteristic peak: δ 6.10 (1H, s, heterocyclic CH);

ac) Ethyl 3- [3- (acetylthio) -1-oxopropyl] -2,3-dihydro-5- (naphth-2-yl) -1,3,4-thiadiazole-2-carboxylate; mp 107-108 ° C;

ad) 5- (Adamant-1-yl) -2,3-dihydro-3- (3-mercapto-1-oxopropyl) -1,3,4-thiadiazole-2-carboxylic acid, m.p. 183-184 'C;

ae) 5- (tert-Butyl) -3- {N- [1- (R) -ethoxycarbonylbutyl] -L-alanyl} -2,3-dihydro-1,3,4-thiadiazole-2- (R) - carboxylic acid, m.p. 67-69 ° C;

af) 5-Cyclohexyl-2,3-dihydro-3- (3-mercaptoxo-propyl) -1,3,4-thiadiazole-2-carboxylic acid dicyclohexylamine salt, m.p. 174-176 ° C;

ag) 2,3-Dihydro-3- (3-mercapto-1-oxopropyl) 5- (methylthio) -1,3,4-thiadiazole-2-carboxylic acid dicyclohexylamine salt, m.p. 150 -153 ° C;

ah) Benzyl-3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl} -2,3-dihydro-5- (methylthio) -1,3,4-thiadiazole -2- (S) -carboxylate, NMR (CDCl3) characteristic peak δ 2.55 (3H, s, -SCH3) and 6.32 (1H, s, heterocyclic CH).

Claims (4)

Patent Claim Point A process for the preparation of a compound of formula I wherein the C atom represented by * can have the R and S configuration, Y is sulfur, oxygen or NRg - wherein when Y is sulfur or NR9, n is 1, if Y is oxygen or sulfur, n is 0, R9 is C1-C4 alkyl, R 3 is C 1-6 alkyl, C 3-10 cycloalkyl, -SR 10, pyridyl, furyl, morpholino, -NR 4 R 5, phenyl or C 7-10 phenylalkyl, naphthyl, while phenyl may be optionally substituted with C 1 -C 4 alkyl, trifluoromethyl, halogen, C 1 -C 4 alkoxy, or -SR 0, R 1 -C 4 alkyl, R 4 is hydrogen, R 8 is 1-4. C 1 -C 4 alkyl, R 1 -C 4 alkyl, R is hydrogen, (C 1 -C 4) alkyl or (C 1 -C 6) alkyl substituted with amino; Z is R ₂ CH (COOH) NH- or R ₁ SCH 2 - wherein R 1 is hydrogen or ReCO-, wherein R 8 is C 1 -C 4 alkyl, - R 2 is C 1 -C 5 alkyl or C 7 -C 10 alkyl. phenylalkyl, and their pharmaceutically acceptable salts, C 1 -C 4 alkyl esters or C 7 -C 10 phenylalkyl esters, characterized in that a compound of formula II wherein Y, n and R 3 is as defined -, its salt ester or tautomeric form with an optionally protected compound of formula (III) wherein Z and R are as defined and X is a leaving group - or an amino group thereof in R or Z; reaction with a protected derivative of -COOH in the compound of formula I, optionally converting the resulting compound of configuration R into the corresponding configuration of S cleavage of the amino protecting group and optionally removing the thiol and / or carboxylic acid protecting group or groups from a compound of formula (I) and / or converting a compound of formula (I) into a pharmaceutically acceptable salt or ester or in the opposite direction. 2. A process according to claim 1 for the preparation of compounds of formula I wherein Z is R2CH (COOH) NH- and R3 is C1-6alkyl or C3-10cycloalkyl, wherein the appropriately substituted starting material is compounds. A process according to claim 1 for the preparation of a compound of formula (I) wherein: Z is R ₂ CH (COOH) NH-, Y is sulfur, R is methyl or aminobutyl, n is 0, R2 is n-propyl or phenylethyl, R3 is a t-butyl group and the asymmetric carbon atoms have the S-configuration, characterized in that the appropriately substituted starting compounds are used. The process according to claim 1, which is 5- (tert-butyl) 3- {N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine} -2,3-dihydro-1, 3,4-Thiadiazole-2- (S) -carboxylic acid, 5- (tert-butyl) -3- {Na- [1- (S) -carboxy-3-phenyl-propyl] -L-lysyl} -2,3- dihydro-1,3,4-thiadiazole-2- (S) -carboxylic acid and 5- (tert-butyl) -3- {N- [1- (S) -ethoxycarbonyl-butyl] -L-alanine} '2 , 3-dihydro-1,3,4-thiadiazole-2- (S) -carboxylic acid. and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used.